Washington University professor Paul Shaw is cracking the mysteries of sleep

Someday, if Shaw gets his way, cops and doctors will be able to determine sleepiness through a simple spit test.

Washington University professor Paul Shaw is cracking the mysteries of sleep

Paul Shaw sleeps eight hours a night, though he allows himself an extra 45 minutes to drift off. He goes to bed and gets up at the same time every day. He's been doing this for so many years, he no longer needs an alarm clock. He keeps one by the bed anyway, but makes sure it faces the wall so he can't psyche himself out by calculating how much sleep he's losing. At night, his bedroom stays completely dark, and he's trained his cat not to disturb him. He doesn't drink any caffeine after noon.

If you are one of the world's preeminent sleep researchers, as Shaw is, and if you identify yourself as a sleep evangelist, as Shaw does, these are the sort of things people want to know about you. When Shaw goes to a party and doesn't feel like being cornered for several hours discussing other guests' sleep issues, he tells people he's a neuroscientist. Sometimes, just to totally kill any interest, he adds that he works with fruit flies, known in biological circles as Drosophila melanogaster.

Shaw is 48, slight and wiry, with spiky graying hair. Because he gets the proper amount of sleep, and because he keeps a coffeemaker within easy reach of his desk at Washington University, where he's an associate professor of neurobiology, he has plenty of energy, which generally takes the form of talking nonstop at high speed and engaging in rapid-fire argument with anyone who disagrees with him.

Because he works with fruit flies and regularly uses phrases like "fly husbandry," he's developed a sense of humor about his work. He's also learned to defend himself against teasing from his college buddies. He refuses to take academic hierarchies seriously and always keeps his door open. He once cracked himself up writing a grant proposal arguing that his flies were actually models for killer whales. "It did not go over well," he reports. "I wanted to take a bad idea and run with it."

But when it comes to the nation's sleep-deprivation epidemic, Shaw starts raving like a televangelist. It's hard to argue with him. Most people don't get enough sleep. They're tired. They're cranky. They talk wistfully of naps.

For Shaw, sleep deprivation is a national crisis. Few things get him as worked up as reciting statistics from a report by the National Highway Traffic Safety Administration: 62 percent of drivers have reported driving while sleepy, and 27 percent say they have actually fallen asleep at the wheel, which led to 100,000 crashes, 1,500 deaths and $12.5 billion in losses in the year 2000 alone. "And those estimates are low!" Shaw exclaims. "People can't resist the impulse to sleep. It's stronger than the sex drive — unless you're a politician. Driving while sleepy is as bad as driving under the influence of alcohol."

Shaw and his fruit flies are going to change all that. Someday, if Shaw gets his way, there will be ways to determine if a person is sleep deprived. Doctors can test their patients during their annual checkups and prescribe improved sleep hygiene along with better diet and exercise. Shaw's also working on a roadside test like a Breathalyzer that cops can administer to people they've pulled over for driving erratically. Someday he hopes drowsy driving will be as stigmatized as drunk driving.

The key lies in the fruit flies. In Shaw's lab, they're not pests. Instead, they're very tiny models for what goes on inside the human body during sleep. Shaw discovered that both flies and humans produce a protein called amylase. They produce more of it when they're sleepy. In humans, amylase is found in saliva. In Shaw's ideal world, any driver could be outed as sleepy by spitting into a cup. Or by chewing a stick of gum that would change color in the presence of the protein.

Five years ago, when Shaw first published his research about the sleepiness test, the news spread to The Tonight Show where, during an opening monologue, Jay Leno wondered aloud why you can't check to see if someone is asleep by watching their eyelids close.

"It's a valid question," Shaw admits. But he's deadly serious about getting sleepy drivers off the roads — and shaming people into practicing good sleep habits. "You shouldn't put your life in jeopardy. We should hold people accountable with a biomarker. It's that simple."

In order to teach people how to sleep better, of course, it's necessary to find out why they fall asleep in the first place. And that remains one of the greatest, and most fascinating, mysteries of all.

"It's so important," Shaw muses. "We spend a third of our lives doing it. You never feel so bad as you do after a night of sleep loss, and never as good as you do after you get a good night's sleep."

Shaw's colleagues consider him one of the most knowledgeable and astute detectives on the case.

"Paul is poised to crack the problem in function that has eluded us for a long time," says Marcos Frank, who was a post-doctoral fellow with Shaw in San Diego and now runs his own sleep lab at the University of Pennsylvania. "It's a cool question. How come nobody has figured it out?"

It hasn't been for lack of trying.

Over the past 50 years, scientists have slept in caves, far from natural light, so they could map out circadian rhythms. They've meddled with the brains of rats, mice and hamsters. They've kept college students on strict sleep schedules and monitored the effects of both sleep deprivation and oversleeping. They've played with the genetic codes of fruit flies. And they still haven't made much headway.

At the moment, says Frank, the field is at the same stage cardiovascular medicine was before anyone truly understood the circulatory system. "In that situation it was hard to have cardiovascular medicine that made sense. We're missing a vital piece of the puzzle."

Here's what they do know: Every animal sleeps. Birds do it. Bees do it. Animals that live in volcanic vents do it.

There's an amazing variety of ways animals can sleep. The big brown bat sleeps for twenty hours a day. The giraffe sleeps for four. Newborn puppies sleep constantly. Newborn killer whales don't sleep at all. (They spend the first three or four months of their lives swimming with their mothers to their feeding grounds.) Humans dream. Dolphins do not.

And then there is the fruit fly. Which actually does sleep. Shaw was among the first to prove it a decade ago, when sleep researchers first started experimenting with flies. "Sleep is a quiescent state with a higher arousal threshold," he says. So if a fly's not moving, it could be sleeping. Or it could be dead. The only way to determine which is by trying to wake it. "If you can't wake up," Shaw observes, "you're not sleeping." Good to know.

Shaw will not even attempt to answer the question of whether fruit flies possess anything like consciousness. "By broaching the subject," he says, "you bring in a wider variety of people: biologists, psychologists, philosophers, guys on LSD, all with their own agenda and ready to beat the crap out of each other. It's a lose-lose situation."

So let's just stick to the basics. Fruit flies sleep. And even though they don't dream, and even though their brains are far less complicated than humans', the biology is very similar.

"Some areas of the brain are more active during sleep," says James Walsh, executive director of sleep medicine at St. Luke's Hospital in Chesterfield and of the Academic Alliance for Sleep Research. "It needs to become active to disengage from sensory systems. When you're asleep, you don't see as well. You're not as sensitive to tactile stimulation. You're partially detached from your environment. But a portion of the brain has to remain active for the purpose of maintaining sleep."

But why make such an effort at all? Allan Rechtschaffen, Shaw's PhD advisor at the University of Chicago, famously wrote that "if sleep does not serve an absolutely vital function, then it is the greatest mistake the evolutionary process ever made. When we sleep, we do not procreate, protect or nurture the young, gather food, earn money, write papers, etcetera."

Rechtschaffen's observation has become a goad to the rest of the field. "There may be one central function that sleep does for all animals, but no one has proven anything," says Frank. "The field is replete with grand theories. They all founder."

The prevailing theory now, formulated by Giulio Tononi, who worked with Shaw and Frank in San Diego and who is now at the University of Wisconsin-Madison, is that sleep reinforces learning and consolidates memories. In waking life, the brain is constantly growing and changing, building new connections, called synapses, to accommodate new information. But if the brain never bothered to get rid of unused synapses, it would grow too large to fit in the skull.

Sleep is when the brain does its big housecleaning, strengthening the synapses that have been most active during the day and cutting the ones that haven't been used at all. So if you really want to learn something, the best thing you can do is get a good night's sleep. (Shaw wonders, idly, if someday college lectures will conclude with a short nap so all the information can sink in.) Shaw's research shows that the same principle holds true for fruit flies.

Theory aside, two things are certain: If an animal doesn't sleep, it will die. If it doesn't sleep enough, its entire body will go haywire. Anyone who has ever gotten a bad night of sleep knows this. You can't concentrate. You get cranky. You start craving sugar and carbs because the systems that regulate glucose and insulin stop working efficiently. If a string of sleepless nights goes on long enough, you gain weight, your blood pressure goes up, and you run a high risk of developing diabetes. ("The three things a primary care physician says most," notes Matt Thimgan, a former postdoc in Shaw's lab who recently started his own lab at the Missouri University of Science and Technology in Rolla.)

The human body can adjust to a lot of things. It can get used to running several miles a day. It can get used to eating less — or more. It can get used to high temperatures. There are only two things it can't get used to: low temperatures and a lack of sleep.

That doesn't mean we don't try. In 1982 the American Cancer Society surveyed 1 million people about their sleep habits and learned that the vast majority slept between six-and-a-half and nine hours a night. (A followup five years later determined that those who slept seven hours had the longest
lifespans.) But many more fancy themselves members of the small group that can go for only four or five hours with no adverse effects. They see going without sleep as a sign of mental toughness.

It's not: A 2003 study at the University of Pennsylvania showed that at the end of a two-week period of sleeping for only six hours a night, research subjects were the cognitive equivalent of legally drunk.

"A lot of the American public is not getting enough sleep — by choice!" Shaw says indignantly. "They stay up late to watch Leno and Letterman, and then they get up earlier and earlier. And there are consequences."

Like his colleagues, Shaw wants to discover the ultimate reason — or reasons — why we sleep. But, more important, he wants to make sure that people realize just how dangerous it can be go without sleep.

"There are few things you can study," he declares, "that have such huge ramifications."

Shaw wasn't always a sleep evangelist. As a college student at Niagara University in upstate New York in the early 1980s, he studied psychology and criminal justice and prepared for a career in the army, attending airborne school and basic training.

"At airborne school," he recalls, "if you sleep, they beat the crap out of you. You had an acute sense that you shouldn't fall asleep." That sense followed him to basic training, where he spent seven nights out in the woods, surviving on naps. On the final day, he had a class on weapons training.

"This Green Beret guy was showing us all these guns. We were sitting on the forest floor with our buddies, back to back. I started to fall asleep. A voice in my head said, 'If you fall asleep, you'll get in trouble.' But I felt such an overwhelming sense of bliss. I had a choice to stay awake or fall asleep, and I fell asleep. Fortunately, my buddy woke me up."

Twenty days before Shaw was scheduled to be commissioned, the army gave him a medical discharge because of a knee injury he'd suffered before basic training. It hadn't impeded his performance any. He learned later that the army had greatly underestimated the number of people who would be interested in a free college education in exchange for a few years' service.

"So there I was," Shaw remembers, "with all these green suits and nowhere to go." He went home to San José and started studying for a master's degree in psychology at San José State University. Along the way, he became interested in neuroscience. Someone told him that if he was interested in applying to PhD programs, he would need to get some research experience. San José, in those days, was not a major hub of research. The only scientist who was willing to allow Shaw into his lab was Robert Hicks, who just happened to study REM sleep.

"It grabbed me by the throat," Shaw says now. "There was so much to like about sleep. It was my first experience in science and, with luck, it'll be my last."

During his years in Chicago with Rechtschaffen, Shaw worked with rats. He did not like them. He also did not like mice. "Mice are squirrelly, crappy animals," he grumbles. "They're bizarre. They're high cost and high risk."

Fortunately, in the late '90s, he stumbled upon the fruit fly. Strange as it seems, if you're interested in sleep on a genetic and molecular level, like Shaw is, fruit flies are an excellent model for humans. The entire fly genome — 18,000 genes — has been mapped, and 80 percent of those genes have human equivalents. It's even possible to swap human genes into fly DNA — insulin receptors, for example — and they'll work.

The chief advantage in working with flies, though, is that they're cheap and fast: "They live 60 to 70 days in the lab, and they have a ten-day breeding cycle," Shaw explains. The genetics are simple. You can move quickly and take advantage of the momentum as soon as you get an idea. With a mouse study, you have to discuss it and do all sorts of protocol and present it to the review board, and then, months later, you can do the experiment. The excitement is lost."

There are disadvantages. "I sometimes get stowaways," Shaw jokes. "Whenever anyone criticizes my diet, I say I can't have fruit in the house because of the stowaways, but no one believes me."

The flies primarily live in test tubes in the warm room, a small temperature-controlled cube behind a locked door in the Shaw lab's suite of offices on the Wash. U. medical campus. The room has a strong, vinegary smell of fly food. (Actually a mixture of cornmeal, molasses, agar, sugar and yeast, it's the color and consistency of cold, creamed coffee.) Behind the warm room is the sleep room. Eighty-two activity monitors hold ranks of test tubes: 32 tubes per monitor, one fly per tube. A red beam shines through each row of tubes. If the beam is broken, it means the fly is moving and, therefore, awake.

The flies are omnipresent throughout the rest of the lab. They hover in clouds over the long black lab benches where the postdocs and techs splice strands of DNA and tabulate data, and over the workroom where work-study students transfer flies between test tubes for breeding. A few stray through the open door of Shaw's office. They circle past the model surfboard, a souvenir of Shaw's California youth, a baby picture of Shaw's son Nathaniel (now three) and the copy of the picture book Hi! Fly Guy propped up on a shelf. Shaw is so used to the intruders, he doesn't bother to bat them away.

A lab technician can manipulate a single gene in the fly to express a desired trait, and then, a few days later, Shaw and his team will have an entire mutant colony. The flies all come from a lab at Indiana University in Bloomington. Shaw also swaps mutant strains with colleagues across the country, via FedEx.

A few years ago there was concern that the lab flies had been overbred and bore very little similarity to wild fruit flies. An expedition was organized to local wineries to collect samples. (It was a real hardship assignment, says Thimgan.) Though the lab flies and the winery flies were genetically identical, Shaw, fearing infection, continues to get his specimens from Bloomington.

In the early phases of Shaw's research, the flies were mostly valuable for what they could tell him about genetics and how different organs develop. Lately, though, he's begun to branch out into behavior.

In a recent experiment, published in the journal Science in June, Shaw and his lab tried to prove that sleep is, in fact, essential to learning. They took a male fly, genetically modified to fall asleep when one part of its brain was heated to 88 degrees, and put it in close quarters with another male fly genetically engineered to give off female pheromones. The first male fly attempted to do what came naturally, and was rebuffed. The process was repeated an hour later, with the same results. Then the researchers raised the temperature and put the fly to sleep for four hours. When the fly woke up again, the scientists paired him up with an actual female. But the fly remembered that the ladies — or what he believed to be the ladies — didn't like his moves, and stayed away. He still remembered the lesson a few days later. But the flies that did not sleep still tried to mate.

"This is a good test because mating is something flies already do," Shaw says triumphantly. "It's a necessary adaptation for animals to figure out good and bad mating targets."

The general hope in sleep studies is that what Shaw is learning about flies can be translated to mice and, eventually, to humans. Many doctors, though, are still unaware of his work; there's a very large disconnect between researchers and clinicians.

"Clinicians have no interest in fundamental principles," explains James Walsh, himself a clinician. "Most people are busy taking care of patients and want things that help now. They're not interested in a new drug that may evolve in five years and be able to help someone in ten." Not that this sort of myopia is limited to clinicians: "Many basic researchers do occasionally extrapolate beyond their species, but not as much as Paul. His fly work is driven to understand human problems as much as the neurobiology of the fly. The fact that he thinks as much about humans and clinical issues as he does about the neurobiology of the fly is one of his great strengths."

Shaw himself occasionally grows frustrated by what he perceives as the indifference of clinicians. A few years ago, he took a batch of day-old fruit flies and kept them awake for 24 hours. (Fruit flies, like humans, stay awake with heavy doses of caffeine and constant motion; in the case of the flies, this means tilting a test tube at a 60-degree angle, which forces the flies to keep walking to maintain their balance.) The flies were permanently learning-impaired. Shaw immediately saw the implications of his study for humans.

"It's scary," he says. "There are a lot of kids with sleep apnea who are undiagnosed. It takes time for the parents to begin to worry, and they take their time getting the kids to the sleep doc. The longer you wait with a kid, its IQ may never normalize. We're a fly lab. We're not clinicians, but I know clinicians, and they're surprised that kids have sleep apnea and no one's noticing."

Shaw listens to the flies. "The flies tell us what's important," he says.

And what the flies say can be very different from what Shaw expects. "A lot of what we do is wrong," Thimgan admits.

"I stumble onto results," Shaw says. "It's like what Yogi Berra said: 'You'd be surprised by what you can see by looking.' We get a lot of unexpected results. We can blow them off, work more on them or jump to conclusions if one conclusion sounds exciting."

If an experiment does prove one of Shaw's hypotheses, his next step is run another experiment to prove that same hypothesis wrong. "If it doesn't work, it doesn't mean you're right," he says, "The idea is never to be entirely wrong."

Willingness to try the extra experiment, says Marcos Frank, is what makes Shaw rare among scientists. "A lot of people are brilliant," he explains, "but they don't want to put in the legwork to do the hard thing: to design an experiment to prove they were wrong and dash their beautiful dream."

Recently, Shaw's amylase experiment hit a few snags. He proved that amylase levels in saliva increase when a person is tired, but he found that they also go up after a person has eaten a ham sandwich or, more significantly for the project, when he or she is anxious. Which is exactly how most people feel when a cop pulls them over. The anxiety spike goes away after about fifteen minutes, which is about how long it takes to process a license, so conceivably the amylase check could come later.

Unfortunately, when Shaw tested base-line amylase levels in several human subjects, he learned that they varied widely enough that "tired" in one person could simply be "normal" in another.

"We need a panel of biomarkers," he admits. He and Thimgan have devised a new series of experiments to search for a threshold in adults where the biomarker will behave the same for everyone, regardless of base-line levels.

Meanwhile, he continues to work on other projects. The Shaw lab is unusually productive. In recent papers, the researchers have shown that flies that are more social are more receptive to learning, that sleep loss can exacerbate the onset of Parkinson's disease in flies, that fly neurons look different after sleep and sleep deprivation and that flies in starvation mode can go without sleep for several days without adverse effects.

Shaw talks constantly about his pet theory, that sleep is the primordial state. As he puts it, "The first organism was sleeping and evolved wakefulness."

But he has sworn never to publish anything about it. "When you have proven an idea to yourself, you spend your life defending that idea," he explains. "I see it in older colleagues. They spend seven or eight years defending an idea. I'd rather work."

That hasn't prevented Shaw from sharing this theory with his fellow sleep researchers. One of its chief opponents is Jerry Siegel, who runs a sleep lab at the University of California, Los Angeles. Siegel also discounts Allan Rechtschaffen's entire theory that sleep runs counter to evolution. Instead, he believes that sleep is an adaptive state, that animals have adjusted their sleep patterns to accommodate the amount of time they need to look for food. Shaw's experiment that proved that starving flies can go without sleep supports this, he argues.

"I don't see why Paul doesn't pay more attention to his own data," he says sadly. "When you deprive drosophila of food, they become more active. They don't display normal sleep behavior. When you feed them, there's no sleep rebound. Evolution has enabled them to do something to adapt to when there's no food. They look for more food and dispense with sleep."

Most of Siegel's work has been with sea mammals. He was the one who discovered that newborn killer whales don't sleep at all. Their mothers don't sleep, either; during the three-to-four-month journey to their feeding areas, they swim alongside the calves, nursing and protecting them. ("I like to joke that humans think their babies keep them from sleeping," Siegel says. "With whales, it actually happens.") Once the whales reach the feeding grounds, they revert to normal whale sleeping patterns, eight to ten hours a night of floating near the surface. They don't die, and they don't seem mentally impaired. They don't even try to make up for all the sleep they lost.

Ergo, Siegel believes, Shaw is wrong. If sleep really were a primordial state, neither the whales, nor Shaw's fruit flies, would be able to go without sleep.

Shaw laughs when he hears Siegel's argument. "It's always fun to talk to Jerry at conferences," he says. (One imagines them in an academic-conference variation on the barber shop scene in The Great Dictator, each talking over the other and trying to raise his Aeron chair higher so he can look down on his opponent.) "But he has to read my papers more carefully. The real situation is that if you don't sleep, you die. If waking is so good, how come if we don't sleep, we die? I haven't published my own data yet, but [the starving flies going without sleep] doesn't last forever. There's a time limit, and when it's up, there's trouble. So sleep is a primordial state. Ha!"

Whether sleep is primordial or not, Shaw is trying to find the threshold of how long you can go without it without doing irreparable damage. It is, of course, far easier to test the limits of sleep on the flies. He's been working on engineering a superfly that sleeps half as much as a regular fly. "If there's a mutant that can go without sleep, is that good or bad? It's bad if the fly is impaired. Is the fly able to learn?"

Someday, maybe this knowledge can be transferred to humans as well. In dystopian science fiction, there are brigades of robotic, non-sleeping supersoldiers. Shaw's vision is more benign.

"We need to think of ways to keep people functioning. I heard a story about the earthquake in China a couple of years ago on NPR. They interviewed an administrator who hadn't slept in two weeks. What kind of decisions was he making?"